ENDOZEPINE 4--A NATURAL BENZODIAZEPINE RECEPTOR LIGAND

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Endozepine-4 is a newly identified natural chemical that is active at the benzodiazepine receptor (endozepine), and is neither a benzodiazepine nor a peptide. It is a low molecular weight molecule that has a high affinity for the benzodiazepine binding site of the GABAA receptor and is present in pharmacologically relevant concentrations in human and rat brain. It acts selectively at the benzodiazepine receptor. Like the benzodiazepine receptor agonist, diazepam, it can potentiate GABA-mediated chloride fluxes, and can serve as an anticonvulsant. Furthermore, preliminary studies provide evidence that endozepine-4 can cause encephalopathy, and may be the cause of idiopathic recurring stupor and may contribute to hepatic encephalopathy. The proposed studies will examine the role of endozepine-4 in the pathogenesis of idiopathic recurring stupor and hepatic encephalopathy. An animal model will be used to investigate how human and rat endozepine-4 causes encephalopathy and whether these actions occur via the benzodiazepine receptor. (l) We will identify alterations in endozepine-4 in patients with idiopathic recurring stupor and hepatic encephalopathy and determine whether these changes correlate with the clinical level or temporal course of encephalopathy. Significance: Studying endozepine-4 in serum and CSF from patients with these disorders will serve to define its role in idiopathic recurring stupor and hepatic encephalopathy. (2) We propose to test the hypothesis that alterations of endozepine-4 exist in animal models of hepatic encephalopathy and that excess endozepine-4 can cause encephalopathy and therefore contribute to the disease. Significance: Animal models of excess endozepine-4 and animal encephalopathy models will allow us to directly test the hypothesis that endozepine-4 can cause or contribute to encephalopathy. (3) We will test the hypothesis that the behavioral actions of endozepine- 4 are mediated via benzodiazepine receptors by examining its anti-anxiety and anti-convulsant properties. Significance: These studies will determine if naturally occurring endozepine-4 has the functional properties of other synthetic benzodiazepine agonists - anxiolytic and/or anticonvulsant. It is anticipated that the results of these experiments should provide important information on a new neuromodulator that may be an important cause or contributor to certain encephalopathic diseases. Endozepine-4 may also be an important allosteric regulator of GABAergic networks in the nervous system. In addition, the possibility that it could serve as a new class of "natural" anticonvulsants adds additional impetus for its study.